Synthetic androgens, 13-methyl-aceto polyhydrophenanthrene derivatives and preparation thereof



nited States Patent SYNTHETIC ANDRGGENS, 13-METHYL-ACETO POLYHYDROPHENANTHRENE DERIVATIVES AND PREPARATION THEREOF Nicholas Thomas F arinacci, New York, N. Y.

No Drawing. Application September 18, 1956 Serial No. 610,625

26 Claims. crass-46s This invention relates to A(8,14) unsaturated Z-aceto- IS-methyl polyhydrophenanthrones-7 and those having other such 2-substituents as are set forth herein, and to the production, thereof, from pine resin acid derivatives and such of their derivatives whose preparation is described in the referred to herein copending applications. Particularly, this invention relates to 13-methyl-acetoand esterified or free carboxy-polyhydrophenanthrone derivatives of the type such as wherein the m, t and p substituents in II or III are selected from the group consisting of halogen and hydrogen, and R is selected from the group consisting of hydrogen, alkyl and aryl residues, and the preparations, thereof. The COOR group in III may be replaced by a group such as -COCH .CHpCH t, CHOHCH -CH=CH or CHOHCH OH, in accordance with appropriate modifications of the invention and variations thereof.

I have discovered a process for the manufacture of said polyhydrophenanthrene derivatives which involves rearrangement-dehydration and oxidation reactions of nuclearly saturated and nuclearly unsaturated tertiary diphenyl carbinols of the ahietyl and d-pimaryl group and of such as the corresponding aceto polyhydrophenanthrene tertiary carbinols of the type, such as, for example, nuclearly saturated halogenated H2O O OH P11 Ph wherein Ph is phenyl and at least one of the 5, in and 1 groups being halogen and the other a member of the 2,830,074 Patented Apr. 8, 1958 group consisting of halogen and hydrogen and R is a member of the group consisting of (=0) and (H CHa) which are prepared and described according to copending applications Serial Nos. 198,8934-5, filed December 2, 1950, and corresponding applications Serial Nos. 416,433-4 (refiled as applications Serial Nos. 610,623 and 610,624) and Serial No. 428,852 based thereon, which descriptions and relevant subject matter are hereby incorporated, herein. In general said polyhydrophenanthrene-8-tertiary diphenyl carbinols, having the 2-isopropyl group are prepared by Grignard reaction as with phenyl magnesium halides of the corresponding A(7,8) dihydro-levopimaric alkyl and aryl acid esters, as set forth in detail in such as Examples 1 and 2 of copending application Serial No. 416,433 (refiled as application Serial No. 610,623) and the corresponding carbinol halides are prepared as in Examples 1-3 of copending application Serial No. 416,434 (refiled as application Serial No. 610,624) by halogenation or hydrohalogenation of said nuclearly monounsaturated dihydrolevopimaryl tertiary diphenyl carbinols and in accordance with the method of preparation as set forth in Examples 1-3, copending application Serial No. 428,852, the 2-isopropyl group of said carbinol halides is selectively oxidized with hexavalent chromium compounds to provide the corresponding Z-aceto halogenated-l3-methyl polyhydrophenanthrene-B-tertiary diphenyl carbinols, said 2-aceto-carbinols exemplified, for example, in the starting material of Example 3, herein.

The rearrangement-dehydration and oxidation steps involve the reaction of said tertiary carbinols with suitable water abstracting agents such as toluene, acid anhydrides, acyl halides and the like and reaction of the resulting rearranged carbinol dehydrates with suitable oxidizing agents, preferably, such as the hexavalent chromium compounds in neutral or acidic medium, preferably, in an organic carboxylic acid such as glacial acetic acid or its anhydride at moderately low temperatures for a period up to several hours.

Although a preferred scheme for the rearrangementdehydration and oxidation process of this invention comprises reaction of a nuclearly saturated halogenated abietyl or di-pimaryl type of tertiary diphenyl carbinol with an excess of dehydrating agent such as phosphoric pentoxide in such a glacial acetic acid at temperatures below C. to effect first rearrangement-dehydration and then reaction with a mixture comprising a hexavalent chromium compound such as CIO;.; and an orthophosphate-ion pro ducing compound such as orthophosphoric acid or an anhydride thereof, at temperatures preferably below 50 C., to effect oxidation of the rearranged carbinol dehydrate, it will be immediately apparent to one skilled in the art that specific reagents and the proportions and concentrations of reactants, as well as temperatures and periods of the reactions, may be varied within wide limits and that the alkane carboxylic acid reaction-medium may be replaced by inert acid anhydrides or by suitable inert solvents such as chloroform, carbon tetrachloride, acetone and the like. For example, rearrangement-dehydration and oxidation reactions may be carried out over a fairly wide temperature range, varying from 5 C. to as high as 80 C. or up to C; At the higher temperatures the rearrangement-dehydration and oxidation reactions are completed within a few hours while at 5 C., reaction may require several days to reach completion. The dehydration agents may be such as phosphoric or sulfuric or acetic or anhydrides in general and the like but are not limited to anhydrides and include other suitable waterabstracting agents such as toluene and toluene-sulfonates and such as acyl halides and the oxidizing agents suitably and preferably may be hexavalent chromium compound such as hexavalent chromic oxide, a chromate, bichromate or chromyl compound and mixtures of these agents with inert solvents such as water, alkanoic acids, tertiary alcohols, ketones, hydrocarbons and halogenated hydrocarbons. and their derivatives which are suitably inert with respect to the oxidation step of the invention.

The starting material may be the nuclearly unsaturated abietyl and d-primaryl types of tertiary diphenyl carbinols which comprise thosehaving nuclear monene structures such as the A(6,7) and A(7,8) dihydrolevopimaryl and A(8,14) neoabietyl and. also d-pimaryl nuclei and nuclear dienes A(9,-14) (7,8) abietic and A(14,8) (6,7) levopimaric nuclei and the nuclear triene and tetraene nuclei, dehy droabietyl and A(9,10) dehydroabietyl nuclei, respectively, and thus as desirable or necessary the overall process may include the step of protectively saturating the ring nucleus with addends (with or without isomerization) such as halogens as in Examples 1-4, or halogen hydrides, and said protected derivative may be rearrangeddehydrated and oxidized and the addend removed, if desired, thus simplifying the over all process with steps which comprise additions of such as saturating halogen, rearrangemcnt-dehydration, oxidation and restoring the unsaturated bonds, with suitable intervals and suitable regulation of temperatures, thus effecting acontinuous over all process in one batch.

As known, in oxidations of nuclear diene and monene compounds, some ring cleavage of the C-ring occurs resulting in substituted polyhydronapthalene compounds, namely cleavages across the double bonds in neoa'bietyl, dextropimaryl and levopimaryl, and the corresponding dihydrolevopimaryl monenes. These result in corresponding polyhydronapthalenes having as a substituent on the 1position a member of the group consisting of -CH COOH, CHz--CH2--CO-COOH -CH .-CH --COCH (CH 2 CH -CH CO -CH 1 --CH -CH C CH C H CH CH ,C( q) (CH )COOH wherein q is selected from the group consisting of OH, COCH -CHpCI-I t, and -COOR (wherein R is selected from the group consisting of hydrogen, alkyl, and aryl radicals), and on the 2'-position a member of the group consisting of -CH COCH(CH -CH -(CO) CH =0; and COOH (see Harris et al. Jour. Am. Chem. Soc., vol. 70, pp. 340 and 2083 (1948), and Fieser et al., Natural Products Relatedto Phenanthrene, 3rd ed. (1949), chap. 11, pages 56 and 65,

particularly).

This process also is applicable, as illustrated in examples herein, to isomers of abietyl tertiary carbinols indicated in the examples for the d-pimaryl series'to produce the corresponding 13-methyl phenanthrones which illustrations are noted to refer to the overall process starting from the pine resin acid esters and illustrative therein, of the utility of inventions in the several copending applications as applied to the d-pimaryl types of compounds.

The products which are produced from thehalogenated dihydrolevopimaryl tertiary diphenyl carbinols include the corresponding halogenated aceto-phenanthrenes having the formula wherein at least one of the m and t groups being halogen and the other a member of. the group consisting of halogen and hydrogen. This may be isolated from the organic residue obtained from the reaction mixture by purifying with such as petroleum ether and alkali, washing to separate the neutral halogenated oxidized products, therefrom. The unsaturated aceto-polyhydrophenanthrone having the formula it 2 -C-CH3 may be obtained by dehalogenating with zinc in acetic acid, or with sodium iodide in alcohols, and the like or by dehydrohalogenating the monohalides with pyridine bases and the like. i

The new said l3-methyl-2-aceto'7-keto polyhydrophenanthrene IV, of this invention promotes combgrowth in capons and therefore has androgenic hormonal properties. This product and itsderivatives may serve as intermediates for the manufacture of some of the conventional steroid hormones as may also the other phenanthrones described herein, since these compounds particularly have the steroid type of configuration.

The androgenic hormones have been used for the purpose of controlling pituitary 'gonadotrophin secretions. Thus, androgenic hormones such as testosterone and the like, in certain dosages, are known to inhibit pituitary hormone secretion and also to provide beneficial metabolic functions. production of androgenic hormones from sterols and saponins is relatively very costly. Thus the economical production of audrogenically active hormones having this compositions of this invention are useful and valuable in p tein anabolism in animals and man.

. desirable.

property of male gland hormones is therefore highly It is an object of this invention to provide new .androgenically active substances at low cost and corresponding useful intermediates for conventional hormone production.

The aceto polyhydrophenanthrones and derivatives thereof, which are comprised in this invention are new and useful compositions in the field of therapeutics by virtue of their ability to affect secretion of hormones by the pituitary gland and their androgenic properties and metabolism-affecting properties. More particularly, new

medicine for the control of certain glandular disorders because they are androgenically active.

The androgenic hormones in addition to their specific effects on the sexual and reproductive systems have other general metabolic etfects. The androgens stimulate pro- This valuable property has found wide therapeutic use. The substances of this invention indicate similar metabolic effects in the capon growth cycle and fulfill the need for the economical production of metabolism-stimulating androgenic materials. It is to be understood that the utility of the substances described and claimed in this application is not dependent on the mode of action, thereof, or on the current knowledge and theories relating to physiological processes.

Acetopolyhydrophenanthrones and derivatives thereof,

' may be prepared in accordance with the invention from suitably. constituted abietyl type of tertiary diphenyl carbinols and the corresponding aceto-polyhydrophenanthrene tertiary carbinols as specifically disclosed and illustrated in the following examples (quantities of reactants are given in part by weight). Included therein, are the dehydroabietyl type of tertiary diphenyl carbinols. The suitably constituted d-pimaryl type of tertiary diphenyl carbinols also may be'converted to corresponding phenanthrones by the process of this invention, that is, 7-aceto and 'J-glycol d-pirnaryl tertiary diphenyl carbinols However, it is well known that the usual provide corresponding 2raceto polyhydrophenanthrones. The said 7-acet0-, and 7-glycol-d-pimaryl tertiary diphenyl carbinols, respectively, are generally prepared as by selective oxidation. with hexavalent chromium compounds of the 7-side chain of the corresponding Z-hydroxyethyl- 2,13-dimethyl-l1,1-halogenated (or hydrohalogenated) polyhydrophenanthrene-8-tertiary diphenyl carbinol and of the 2-vinyl side chain of the corresponding carbinol as with dilute permanganate and thereby to produce, respectively, the corresponding said 2-aceto and 2-glycol tertiary diphenyl carbinols as set forth in detail in such as Examples 5 and 4, respectively, of copending application Serial No. 428,852.

The, in general, preparation of such as the starting materials 7-carboxy-R d-pimaryl tertiary diphenyl carbinols is as set forth in Example 4, herein, and as set forth in detail in Example 4, of copending application Serial No. 428,852, wherein the preparation of such as 2-carboxyphenyl-l 1-chloro-2,8, l 3 -trimethyl polyhydrophenanthrene-S-tertiary diphenyl carbinol by esterification with phenol of the 7-carboxy-d-pirnaryl tertiary diphenyl carbinol followed by hydrochlorination to produce the said Z-carboxyphenyl derivative and the preparation of corresponding 7-carboxy-R d-pimaryl tertiary diphenyl carbinols such as the corresponding 2-carboxymethyl polyhydrophenanthrene-8-tertiary diphenyl carbinol by esterification of the said 7-carboxy-d-pimaryl tertiary diphenyl carbinol with methanol and esterification with other alkyl and aryl monohydric alcohols to produce corresponding 2-carboxy-R polyhydrophenanthrene-8- tertiary diphenyl carbinols as set forth in said Example 4, of said application Serial No. 428,852, specification, wherein the halogenation and hydrohalogenation procedures for saturating unsaturated derivatives are set forth in detail and generally indicated herein, as in specification, page 5, lines 7-13, and in Examples l-5, herein. The examples are merely illustrative in nature and are not to be construed as limiting my invention. The expressions carboxymethyl, carboxyphenyl and such as carboxy-R are defined herein to indicate an ester group.

Example 1 154 grams of A(7,8) dihydro-l-primaryl tertiary diphenyl carbinol in 3 liters of glacial acetic acid are treated dropwise with 60 grams of bromine in 100 cc. glacial acetic while stirring for one-half hour at room temperature. There is added 115 grams of P while stirring and heating to 70 C. for an hour. The solution of rearranged carbinol dehydrate (tertiary diphenyl methyl compound) (C H Br C=65.l%) cooled to 40 C., is treated with 230 grams of 85% aqueous phosphoric acid and portionwise with 170 grams of powdered CrO with vigorous stirring and temperature control below 50 C. Stirring is continued for at least 45 minutes to complete the oxidation. Chromic phosphate(solvate) is filtered ofi as precipitate and washed to recover organic material. The combined organic material is recovered with ether, dried and washed with petroleum ether, B. P. 30-60" C. The ethyl-ether solution of residue is washed with aqueous alkali and the recovered 120 grams of crude neutral dibromides are debrominated in a liter of glacial acetic acid with 200 grams of powdered zinc added,

portionwise over 3 hours while maintaining temperature of 70 C., and 70 grams of crude unsaturated aceto polyhydrophenanthrone are thoroughly washed with petroleum ether to yield 60 grams of neutral product, from which the A(1,2)(8,14) 7-keto 2-aceto-13-methyl polyhydrophenanthrene, M. P. 126 C., C 78.5%, H 8.6%, mono- 2:4 dinitrophenylhydrazone 12.8% N, di-2:4 dinitrophenylhydrazone 18% N, is recovered.

Example 31 grams of A(7,8) dihydro-l-pimaryl tertiary diphenyl carbinol, prepared as in copending application Serial No. 198,893 (refiled as continuation-impart as application Serial No. 416,433 and as continuation-impart thereof as application Serial No. 610,623), is dissolved in 600 cc. of glacial acetic and treated with 12 grams of bromine in 200 cc. glacial acetic with stirring at 25 to 30 C., for one-half hour. The solution is treated with 100 grams of acetic anhydride and heated to C., while stirring for an hour. 'The solution of rearranged carbinol dehydrate (tertiary diphenyl methyl compound) (C H Br C=65.l%) is cooled to 30 C. and is then treated with a mixture of 20 grams of P 0 and 30 grams of aqueous phosphoric acid and then with 50 grams of powdered K CrO while stirring vigorously and maintaining the temperature below 45 C., over the period of an hour. The chromic phosphate solvate is filtered and washed with ethyl other on the funnel to recover the brominated organic products. The acetic-phosphoric solution of products is diluted with an equal amount of water and the organic material recovered with dichlorethane and freed of solvent under vacuo. The products are freed of acids and thoroughly washed with petroleum-ether as in Example 1, and the 22 grams of crude neutral brominated products are recovered from which a product is obtained by crystallization from ether C H zO Br percent bromine 38.5. This product is treated with 40 grams of zinc dust in 200 grams of glacial acetic between 50 and 70 C., with 15 minutes refluxing after 3 hours. There is recovered 10 grams of neutral product from which the A(1,2)(8,14) 7-l eto 2-aceto-13- methyl polyhydrophenanthrene C H O whose mono 2:4 .dinitrophenylhydrazone derivative sinters at 150 C. and analyzes 12.8% N is obtained.

Example 3 200 grams of 1,2-dibromo-2-aceto-polyhydrophenanthrene tertiary diphenyl carbinol having the formula wherein Ph is phenyl, prepared according to process of copending application Serial No. 198,895 (refiled as Ser. No. 428,852) are dissolved in 3 liters carbon tetrachloride and treated with grams of dry P 0 stirring and heating to 70 C. for one hour, and the cooled solution of the resulting 2-acetol,2-dibr0m-13-methyl A(8,l4) polyhydrophenanthrene-S-tertiary diphenyl methyl, having the formula Ph- Ph wherein Ph denotes phenyl, rearranged carbinol dehydrate (C H OBr 63.5% C.), is treated with grams of 85% H PO and 95 grams of Cr0 at 50 C. for 4 hours as in Example 1. The dried organic residue is washed with petroleum ether and aqueous alkali as in Example 1, to recover the crude corresponding dibrom-aceto-polyhydrophenanthrone which may be dehalogenated to produce the unsaturated A(8,14)(l,2) Z-aceto polyhydro- 75 phenanthtone-Tas in Example "1.

7 ,Example 4 gra ns, of-7-carboxymethyl' tertiary diphenyl carbinol,

, (prepared as described in copending application Serial Ph P-h which ;gives a 62.3% dehydrated rearranged carbinol (C H O Br2), dissolved in 200 grams of glacial acetic acid is treated with 4 grams of bromine with stirring for minutes. There is added 15 grams of H 80, (95%) andhea-t applied to C. for 30 minutes. The mixture ofrearranged carbinol dehydrate, (2-carboxyrnethyl-11,1- dibrom2,13-dimethyl A(8,14) polyhydrophenanthrene-S- tertiary diphenyl methyl),.-is treated with 38 grams of aqueous H PO and lO grams of anhydrous CrO whichis added with stirring over 30 minutes while mainl taining the temperature below 60 C. The organic'residue which is recovered in ethyl ether is washed with aqueous alkali, dried and extractedwith; petroleum ether, dried, then debrorninated with 30 grams of powdered zinc while dissolved in, cc. glacial acetic acid; 3 grams of 7-keto A( 1,1 l (8,14)-2,13-dirnethyl-Z-carboxymethyl polyhydrophenanthrene are recovered as an oily product, C is 75.5%, H is 8.1%, saponification value 196. The phenyl ester may be also used as produced by the este'rification step and according to this example to produce correspond ing carboxyphenyl polyhydrophenanthrone-7.

Example 5 2 grams of l4,8-dibromoJ-aceto-d-pimaryl tertiary 'diphenyl carbinol prepared as described in copending ap-' plication Serial No. 198,895 (refiled as Ser. No. 428,852) is treated as in Example 4, to produce 0.9 gram of A(8,14) (11,1)12aceto-2,l3-dimethy1 polyhydrophenam throne-7a Similarly the'corresponding dihalogenated-7- glycol-d-pimar-yl tertiary diphenyl carbinol is converted to thecorrespondin g A (8,14) -2-aceto-2, l S-dimethyl polyhydrophenanthrene-S-tertiary diphenyi methyl derivative (C gH OBr 63.1% C.),'in the first rearrangement-dehydration step and the invention process applied as in Example 4 produces 1.3 grams of corresponding A(8,14) (11,1) 2-aceto-2,13-dimethyl polyhydrophenanthrone-7, from 3 grams of corresponding carbinol.

Example 6 5 grams of dpimaryltertiary diphenyl carbinol is con- .verted to .a A(5,10) -2,6.-diketo-9-1nethyl polyhydronaphthalene-1-(u-methy1:a;earboxy)butyric acid product by the procedure as in Example 6. The carbinol tetrabromide (or dihydrochloride) in accordance with Examplej3 or 4 provides A(8,14)(1l,1)-7-keto2,13- diinethyl-Z-ethene polyhydrophenanthrene; three grams of: which dissolved in 100 cc.- of a 50-50 mixture of acetone-water solution containing 5% H 50; and stirred for 4 hours atabout 0 C. provide'0.5 gram of the A(8,14),(11,1) 7 keto 2,13 dirnethyl 2 hydroxyethyl polyhydrophenanthrene. Similarly 0.8 gram of the corresponding 2- lycol compound is obtained from 3 grams or the 2ethene compound by stirring with a 100 cc. of a 5% KMnO in a 50-50 acetone-water solution for 3 hours at about 0 C. Accordingly, the substituted polyhydronaphthalenes and compounds or .Formule. ill noted above are produced by such modifications of the invention process. Such compounds are also obtained as side products in the above examples.

The temperature at which the dehydration reaction is carried out will depend on the dehydration agent. For

' example, with acetic anhydride the dehydration is carried out at a temperature of above 60 to 0, with toluene a reflux temperature of about 110 C. is used and with milder dehydrating agents the temperature of dehydration, for example, anhydrous chromic acid without addition of other dehydrating agent both the dehydration and oxidation may be carried out at as high as C. The acyl halides permit lower temperatures for effective dehydration in the range of about 5 to about 55 C. and the use of a dehydrating agent which is insoluble in the reaction medium requires that effective contact of the carbinol with the solid phasecontaining the dehydrating agent is made. i

The nomenclature, numbering, structures and configuration are defined in this specification and claims for the phenanthrene series to conform with those of 1 our. Am.

Chem. Soc. 55 3905 (1933), and those for the abietyl wherein ?h is phenyl, 1, t and s are each selected from the group consisting of halogen and hydrogen, in is selected from the group consisting of hydrogen, halogen and methyl and n is selected from the group consisting of -'CH(CH -COCH CH=CH -CHOHCH 'CHO C 0H, -COOR (wherciniR is selected from the group consisting of hydrogen, alkyl and aryl radi cals) and -CHpCH t (wherein p and t are each selected from the group of halogen and hydrogen). Ring A is def ned to have substituents-B,lS-dimethyl-S-tertiary diphenyl carbinol and the indicated structure. In accordance with embodiments of the invention overall process illustrated as in examples herein, in general, the carbinols on mixingwith dehydrating agents and heating are converted to corresponding rearrangecl-carbinol-dehydrates, the tertiary diphenyl methyl derivatives, .which include A B p and compositional formula (C H smntp wherein Ph, p, t, s, m and n are defined as in the above and having inring A the substituents l3-methyl-8-tertiary diphenyl methyl and indicated structure.

It is contemplated the invention, herein, broadly is applicable to tertiary diphenyl carbinols containing the bicyclic ring residue having the formula wherein the angularmethyl group and the tertiary diphenyl carbinol group are deemed to .be in trans relation with each other. The tertiary diphenyl carbinols derived from the abietyl and d-primaryl groups of the phenanthryl series of compounds are found to have said residue in which angular methyl and tertiary diphenyl carbinol groups are deemed to be in trans relation with each other. Such tertiary diphenyl carbinols, approximately, are contemplated as suitable for the invention herein, particularly, such as the halogenated and acetotertiary diphenyl carbinols and the like, disclosed in copending applications (Serial Nos. 198,893-4-5, refiled as Serial Nos. 416,433-4 (and Serial Nos. 610,623 and 610,624), Serial No. 428,852). In general, the invention is applicable to the tertiary diphenyl carbinols of such derivatives of the abietyl and d-primaryl groups as may be substituted by hydroxyl, carbonyl, halogen, carboxyalltyl and the like and which may have saturated or aromatic C rings, including, for example, the related A(9,l0) dehydroabietyl diphenyl tertiary carbinol derivatives wherein conjugated unsaturation extends to the Bring.

It is desirable that for such derivatives of the abietyl and d-pimaryl groups of the phenanthryl series of compounds as may be produced in accordance with the invention from corresponding tertiary diphenyl carbinols thereof, the tricyclic ring system should be intact and by virtue of protective substitution such as with halogenation of the C-ring and also aromatization, thereof, the tricyclic ring system tends to be inert to oxidative fissure, thereof, so that in accordance therewith, such compounds may be produced which have intact tricyclic ring systems and intermediates, following a rearrangement-dehydration step rearranged-carbinol-dehydrate intermediates, the tertiary diphenyl methyl derivatives, are found to be produced having typical A ring structure.

In the second step of the invention, oxidation as set forth 'herein, converts carbinol dehydrates, tertiary diphenyl methyl compounds, to the typical alpha-beta unsaturated ketonic A ring structure In the course of the transformation of such tertiary diphenyl carbinols to such corresponding alpha-beta unsaturated ketones it is contemplated that concurrently dehydration and oxidation may occur at other locations, for example, dehydration of the hydroxylated side chain (-CHOHCH OH) in a d-primaryl-7-glycol tertiary diphenyl carbinol and such as oxidation of isopropyl side chain to acetoas shown in examples, herein, for halogenated dihydro-lpimaryl tertiary diphenyl carbinols. Other concurrent reactions may occur as ketonization of ring and side chain hydroxyls and such as ketonization by allylic oxidation of the 9 position of a dehydroabietyl tertiary diphenyl carbinol to produce corresponding polyk-etones.

In accordance with Fieser and Fieser, loc. cit., definitions and also Fieser and Campbell, loc. cit., the expression, having the double bond adjacent to the isopropyl group conforms to definition of the A(6,7) and A(7,8)dihydrolevopimaryl nuclei, and the term aromatized abietyl refers to aromatic C ring for said abietyl derivatives.

The foregoing may be summarized as follows.

The starting tertiary carbinol may be represented by the formula wherein the angular methyl and tertiary carbinol groups m to f aC O A B \p v Ph--Ph This material is oxidized by means of oxidizing agents, preferably by a hexavalent chromium compound at a temperature in the range of 5 to about C., prefthe intermediate rearranged 11 erably below 80 C., and this produces acyclic. ketone'of the formula In all the foregoing'formulasv is selected from the group consisting of :0, =H andqone end of a double bond, R is selected from the group consisting of --CH -CH --C(q) (CH )COOH, wherein q is selected from the group consisting of -OH, COCH end of said ring forming radical, said ring formingrad ical having the formula 8 cooot wherein w and u are each selected from the group con -v sisting of hydrogen and one end of a double bond, s,

"12 I binols obtained thereby-are converted .to corresponding saturated halides by .halogenation orhydrohalogenation which features and carbinol halide products are det scribed and claimed in copending application Serial No. 610,624, filed Sept. 18, 1956, as a continuation-in-part of Serial No. 416,434, filed March 15, 1954, as a continuation-in-part of application; Serial No. 198,894 filed Dec. 2, 1950, now abandoned.

The resulting carbinol halides and the corresponding C-ring aromatized tertiary ca'rbinols (obtained as above from the corresponding aromatized pine resin acids) are subjected to selective oxidation which converts the 2- side chain of the polyhydrophenanthrene tertiarycarbinol to an alpha carbonyl group, which features and t carbinol products are described and claimed inapplication Serial No. 428,852 filed jMay 10, 1954, as a continuation-in-part of applicatioriflSerial No. 198,'8S 5- file'd Dec. 2, 1950, now abandoned.

The carbinol in the material obtained by any offlthe above discussed methods is rearrangedand dehydrated to provide a tertiary diphenyl methyl compound whereby an (8,14) unsaturated double bond is formed'by'removal of elements of water from the rearranged carbinol and the resulting compounds are oxidized on the active methylene group thereby formed which is adjacent to the said tertiary diphenyl methyl group, to provide the corresponding alpha-beta unsaturated 7-keto polyhydrophenanthrene compounds, which are shown to have androgenic and anabolic activities, which features and compounds are described and claimed in the present application which is a continuation-in-part of applicationaSerial No. 441,646, filed July 6, 1954, which is a .continuatiolb in-part of application Serial No. 198,892 filed ,Dec. 52,

i v 1950, now abandoned. I

t, and p are each selected from the group consisting of 1 hydrogen, halogen and one end of a double bond, m is selected from the group consisting of hydrogen, halogen, methyl, and one end of a double bond, said ends of double bonds being in a position selected from the group consisting of the w and u, s and m, m and t, t and p, and p and v positions, and n is selected from the group consisting of eC(CH (wherein e is selected from the group consisting of hydrogen and one end of a double bond in the e and m position), -COCH --CHOHCH CHOHCH OH,CHpCH t, and --COOR, and Ph is phenyl,

The group of inventions comprised in the copending applications as noted below relates to converting the readily available pine resin acids to materials having androgenic activity, which materials may be further converted to natural cyclopentanopolyhydrophenanthrene type of hormones. They are described and claimed in copending, applications Serial No. 416,433 (610,623),

Serial No. 416,434 (610,624, Serial No. 428,852, Serial No. 441,646 (610,625) and Serial No.390,747 (647,986).

In this overall process an ester derivative ofa ,pine resin acid is converted to a tertiary carbinol by Grignard reaction.

In this connection there are included an improved method for obtaining high yields of carbinol of the order of 95% of theory by operation at elevated temperatures with high boiling solvents, and also a novel. method of recovery of the high yield of desired carbinol product in substantially pure form by degradation and removal of the unreacted acid esters therefrom, and also a method for rearranging and dehydrating the tertiary carbinol products to corresponding.tertiary'diphenyl-methyl compounds. These novel features and intermediate compounds are described and claimed in application Serial No. 610,623, filed Sept. 18, 1956, as a continuation-inpart of Serial No. 416,433 filed March-15, 1954, as a continuation-in-part of application Serial No. 198,893 filed Dec. 2, 1950, now abandoned. 1 v

The class ofnuclearly monounsaturated tertiary car- In the oxidation step, there are obtained as side..products corresponding polyhydronapthone propionicacids and lactones, and these may be converted to the..correspending above mentioned 7-keto polyhydrophenanthuene compounds by treatment with an acetylating agent .asby

with methyl halide magnesium salts) which .featuresand intermediate polyhydronapthalene compounds are .described and claimed in copending application Serial Num ber 647,986, filed March 25, 1957, as a continuatiou inpart of application Serial No. 390,747. filed Now-6,1195% as a .continuation-in-part of application Serial No. 260,231 filed June 6, 1951, both nowabandoned,

The above mentioned 7-keto polyhydrophenanthncnes may be converted to suitable corresponding acetic-.01 propionic .acid ester derivatives which maysbe cyclyzed to corresponding known cyclopentanopolyhydrophenanthrene hormone intermediates, which may be converted by well known methods to natural steroid hormones.

In these fields, two types of nomenclature andnumberw ing are established, (1) in terms of the structural isomers of the abietyl and d-pimaryl types wherein the tricyclic numbering is shown in the formulas given as .carbon skeletons i wherein b is a tertiarily bound group such as -COOR,

--COHPh CH OH and CH NH wherein R and Ph have the definitions setforth herein, and (2) in terms of a polyhydrophenanthrene nomenclature and numbering,wherein the tricyclic numbering is as shown in the same carbon skeletons, as shownin the formula below, both of which continuations-in-part thereof, the refiled applications 86- rial Nos. 416,433-4 filed March 15, 1954 and Serial Nos. 610,623-4, filed Sept. 18, 1956 (all now, abandoned), and Serial No. 428,852 filed MaylO, 1954, respectively.

The preparations for starting materials for this case are described in copending applications Serial Nos. 416,433- 4 (and 610,623-4) and Serial No. 428,852 and (Serial Nos. 198,893-4-5) which descriptions are hereby, incorporated herein.

The materials prepared in accordance with descripa member of the group consisting of COCH and COOR (wherein R is selected from the group consisting of hydrogen, alkyl and aryl radicals) from a corresponding 8,13-dimethyl polyhydrophenanthrene-8-tertiary diphenyl carbinol reactant having as a Z-substituent-a radical, said radical being a member of the group consisting of CH(CH CH=CH CHOHCH CHOHCH OH, COCH and COOR, the nucleus of which carbinol reactant is resistant to rupture byv oxida tion under the process conditions and wherein the 13- angular methyl and 8-tertiary diphenyl carbinol groups are in trans relationship, which process comprises subjecting a mixture of said carbinol reactantwith a dehydrating agent to a temperature in the range of about 5 up to below about 150 0., whereby the elements of water are removed, mixing the resulting product with a hexavalent chromium compound and subjecting the mixtureto a temperature in the range of above about 5 to below about 150 C., whereby the desired ketone is produced.

2. A process of claim 1, wherein there is present in the reaction product resulting from the water eliminating step a corresponding 13-methyl polyhydrophenanthrene-S-tertiary diphenyl methyl compound having at least one nuclear double bond in the 8:14 position and having said Z-substituent corresponding to said carbinol reactant.

3. A process of claim 1, wherein the mixture of carbinol reactant and hexavalent chromium compound is the resulting mixture is subjected to a temperaturein therange of above about 5 and below about 150 C.

4. A process of claim 3, wherein thetemperature is maintained below about 80 C.

5. A process of claim 1, wherein the dehydrating agent is an acid anhydride. i

6. A process of claim 1, wherein the nucleus contains at least one and at most two halogens.

7. A process of claim.6, followed by subjecting the product to the action of a halogen removing agent whereby a ketone having at most fivenuclear double bonds is produced.

8. A process of claim 7, wherein a ketone having an aceto group as a 2-substituent is produced.

9. A process of claim 7, wherein a ketone having at most three nuclear double bonds is produced.

10. A process of claim 8, wherein a ketone having two nuclear double bonds in the 1:2 and 8:14 position is produced. c

11. A 7-keto-13-methyl polyhydrophenanthrene compound having one double bond located in the Aring in the 8:14 position and having as a Z-substituent an a-carbonylated radical, said radical being a member of the group consisting of COCHg, and COOR (Wherein R is selected from the group consisting of hydrogen, alkyl and aryl radicals) and wherein the phenanthrene nucleus contains at most four double bonds located in the B and C rings of the structural skeleton.

COCH;

3O 7 Br -17. A compound having a formula coon.

18. A compound having a formula COOCH 19. A 13-methyl polyhydrophenanthrene-S-tertiary diphenyl methyl compound having one nuclear double bond mixed with an orthophosphate producing compound and located in the A ring in the 8: 14 position and having as a:2-.snbstitu ent and a-carbonylated radical, said radical being mmember of the group consisting of -COCH and-- -C OOR (wherein R is a member of the 1 group consisting of hydrogen, alkyl and aryl radicals) and whereinI-.the;.phenanthrene nucleus contains at most four double bonds located in the B and C rings of the structuralaskeleton V V y -iCHs wherein Ph represents phenyl and a represents the said 2-substituent group.

"20. A cornpound orclaim 19, wherein the nucleus contains at least one and at most two halogens.

21. A co'mpound of claim '19, wherein the-nucleus contains at most three-"doublebonds. v

22. A -compound of claim 19, havingan'aceto group asmZ-substituent. r v

'" 23. t A compound having a formula 1(3Hs wherein Ph represents phenyl. V t

24. A process for the production of a 6-keto-9-methyl polyhy'dronaphthalene compound having-a nuclear double bond located in the A ring 1 in the 55 position and having :a formula 8 1A 7 9 2 R4. SAID 3 0: s 4

wherein R is a member of the group consisting of --CH,-COOH, --CH --CH --CO-CO- -CH (wherein R is selectedfrom the. group consisting of hydrogen, alkyl and aryl radicals) and R is a member of the group consistingof =0, -COOH from an 8,13-dimethyl polyhydrophenanthrene-8-tertiary diphenyl carbinol reactant having as a Z-substituent a radical which is a member of the group consisting of --CH(CH --CH=CH -CHOHCH and .15 -=COCH and -.COOR, the .phenanthrene nucleus of said reactant having atleast one and at most two double bonds located in the C ring of the structural skeleton.

H5O OOH wherein :x.represents the said Z-substituent and Ph represents phenyl, andwherein the 13-angular methyl and 8-tertiarydipheny1.radicals are in trans relationship,

wherein R is a member of the group consisting of --CH --COOH,-CH -CH -CO-COCH CH CH C(CH -COOH) (--COCH and g i CH CH -C(CH (--COOH) (-COOR) (wherein Ris selected from the group consisting of. hy-

drogen,palkyl and aryl radicals) and R is a member of the groupconsistingof =0, .COOH and --CH -CO-CO-CH 26. A compound having a formula m 1i boon ReferenceszCited in the file of this. patent "UNITED STATES PATENTS 2,323,584. Schoeller et al. July. 6, 1943 OTHER REFERENCES Zeiss: J Chem. .Soc., 70, 858 t0'860 194s Zeissr J.:Am. Chem. Soc., 73, .497 to 499 (1951). Kharasch et al.: J. Org.Chem. 16, 447 to 456' (1951). 

1. A PROCESS FOR THE PRODUCTION OF A 7-KETON-13-METHYL POLYHYDROPHENANTHRENE COMPOUND HAVING AT LEAST ONE SUBSTITUENT AN A-CARBONYLATED RADICAL, SAID RADICAL BEING SUBSTITUENT AN A-CARBONYLATED RADICAL, SAID RADICAL BEING A MEMBER OF THE GROUP CONSISTING OF -COCH3 AND -COOR (WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL AND ARYL RADICALS) FROM A CORRESPONDING 8,13-DIMETHYL POLYHYDROPHENANTHRENE-8-TERTIARY DIPHENYL CARBINOL REACTANT HAVING A 2-SUBSTITUENT A RADICAL, SAID RADICAL BEING A MEMBER OF THE GROUP CONSISTING OF -CH(CH3)2, -CH=CH2, -CHOHCH3, -CHOHCH2OH, -CHCH3 AND -COOR, THE NUCLEUS OF WHICH CARBINOL REACTANT IS RESISTANT TO RUPTURE BY OXIDATION UNDER THE PROCESS CONDITIONS AND WHEREIN THE 13ANGULAR METHYL AND 8-TERTIARY DIPHENYL CARBINOL GROUPS ARE IN TRANS RELATIONSHIP, WHICH PROCESS COMPRISES SUBJECTING A MIXTURE OF SAID CARBINOL REACTANT WITH A DEHYDRATING AGENT TO A TEMPERATURE IN THE RANGE OF ABOUT 5* UP TO BELOW ABOUT 150*C., WHEREBY THE ELEMENTS OF WATER ARE REMOVED, MIXING THE RESULTING PRODUCT WITH A HEXAVALENT CHROMIUM COMPOUND AND SUBJECTING THE MIXTURE TO A TEMPERATURE IN THE RANGE OF ABOVE ABOUT 5* TO BELOW ABOUT 150*C., WHEREBY THE DESIRED KETONE IS PRODUCED.
 11. A 7-KETO-13-METHYL POLYHYDRIPHENANTHRENE COMPOUND HAVING ONE DOUBLE BOND LOCATED IN THE A RING IN THE 18:14 POSITION AND HAVING AS A 2-SUBSTITUENT AN A-CARBONYLATED RADICAL, SAID RADICAL BEING A MEMBER OF THE GROUP CONSISTING OF -COCH3, AND -COOR (WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL AND ACYL RADICALS) AND WHEREIN THE PHENANTHRENE NUCLEUS CONTAINS AT MOST FOUR DOUBLE BONDS LOCATED IN THE B AND C RINGS OF THE STRUCTURAL SKELETON
 24. A PROCESS FOR THE PRODUCTION OF A 6-KETO-9-METHYL POLYHYDRONAPHTHALENE COMPOUND HAVING A NUCLEAR DOUBLE BOND LOCATED IN THE A RING IN THE 5:10 POSITION AND HAVING A FORMULA
 25. A 6-KETO-9-METHYL POLYHYDRONAPHTHALENE COMPOUND HAVING A NUCLEAR DOUBLE BOND LOCATED IN THE A RING IN THE 5:10 POSITION AND HAVING A FORMULA 